Extracellular Matrix, Cancer and Therapeutic Targets

Heads: Pr. S. Dedieu and Dr. S. Brézillon

Lines of research

Axis 1. LRP-1: a mechanosensor of the tumor microenvironment

The LRP-1 receptor (low-density lipoprotein receptor-related protein-1) is a multifunctional endocytosis receptor capable of regulating the internalization and catabolism of numerous ligands associated with the extracellular matrix. Our recent work has made it possible to clarify the endocytosis and signaling functions of the LRP-1 receptor and to bring out new functionalities for this receptor, mainly in the control of the adhesion processes of the tumor cell to the extracellular matrix. Through multidisciplinary approaches (biology, physics, imaging), we seek to identify and decipher the molecular mechanisms involving LRP-1-dependent endocytosis during tumor progression.

We are more particularly seeking (i) to better understand how LRP-1 can act as an integrator of signals from the tumor microenvironment, (ii) to validate its relevance as a prognostic biomarker in cancerology, (iii) to develop innovative pharmacological tools targeting LRP-1.

Axis 2. Influence of matrikines on vesicle-mediated intercellular communication

Cancer cells communicate with each other by direct contact or via soluble factors recognized by cell-associated receptors. Recent results suggest the existence of another mode of intercellular communication involving two types of extracellular vesicles: exosomes (40 to 100 nm in diameter) formed by budding of endosome membranes and microvesicles (100 nm to 1 μm in diameter) resulting from the budding of the plasma membrane or blebbing. Their composition and characteristics vary according to the cells from which they originate. They contain proteins, mRNAs and miRNAs that they transfer to neighboring cells, thus modulating tumor progression. They promote angiogenesis and metastatic dissemination by increasing cell migration. They contain proteases involved in the degradation of the extracellular matrix, integrins involved in the tropism of metastasis and matrix macromolecules such as glypican-1, lumican, collagen IV and elastin which have been implicated in the control of tumor invasion.

The objective of this research axis is to study the influence of the Matrikines identified within the laboratory on stromal cells, more particularly endothelial cells, and to analyze their ability to modulate communication between tumor cells and stromal cells ( endothelial cells and fibroblasts) mediated by extracellular vesicles.

Axis 3. Pharmacological innovations

Development of anti-tumor agents from matrikines and matrix cell receptors.

The aim of this task is to develop, in collaboration with our chemist colleagues from UMR CNRS 7312 (Institut de Chimie Moléculaire de Reims) analogs (collagens IV and XIX, lumican) or structural antagonists (elastin peptides) from the sequences and structural data previously obtained concerning the various matrikines studied. We are also exploring the use of these matrikines for the optimization of nanoparticles in the active targeting of tumors.

Peptide TAX2: translational program
The expertise that we have acquired from the network of molecular partners of LRP-1 in a tumoral context (see Axis 1) has prompted us to focus part of our work on thrombospindin-1 (TSP-1). In this context, we have developed the cyclopeptide TAX2, an orthosteric antagonist of the TSP-1:CD47 interaction which offers multiple therapeutic perspectives in oncology and cardiovascular pathologies. In the field of oncology, our work focuses in particular on the characterization of TAX2 as an immunomodulatory agent and its relevance in combined use with immune checkpoint inhibitors.

The TAX2 peptide is the subject of a patent (PCT/FR2012/051593) issued in Europe (EP2729495), the United States (US2014296477), Japan (JP2014525740) and Canada (CA2840719). The patent is licensed to the biotechnology company APMONIA THERAPEUTICS (spin off of the laboratory) in order to accelerate the access of the peptide to the market (first in man clinical trials).


Organization chart